Lisa Edelmann

Icahn School of Medicine at Mount Sinai, Borough of Manhattan, New York, United States

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Publications (45)276.83 Total impact

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    ABSTRACT: Focal facial dermal dysplasias (FFDD) are characterized by congenital bitemporal or preauricular atrophic skin lesions, and either autosomal dominant or autosomal recessive inheritance. Setleis syndrome (SS), FFDD type III, is a severe form of FFDD with the ectodermal lesions plus other striking facial features. Autosomal recessive nonsense and frameshift mutations in TWIST2 have been found to cause SS in some but not all individuals. Here, we report on four unrelated individuals, one with an unclassified FFDD and the other three with classic SS. Chromosomal microarray analyses revealed unique copy number variants of 1p36 in two individuals with duplications at 1p36.22p36.21 and one with a triplication at 1p36.22p36.21. The fourth patient had normal chromosomes by microarray analysis. All four patients had normal TWIST2 exonic sequences. We propose that a dosage effect of one or more of the 30 genes in the 1.3 Mb 1p36.22p36.21 region of overlap is responsible for FFDD/SS manifestations in some individuals, and this mechanism would be inherited as an autosomal dominant trait. In patients with no duplication/triplication of the 1p36.22p36.21 region and no mutations in TWIST2, there are mutation(s) in one of the 30 genes in this region or mutations in other as yet unidentified genes at different locations that may affect the expressions of genes in this region or act independently to cause this developmental disease phenotype. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 02/2015; 167(5). DOI:10.1002/ajmg.a.36973 · 2.05 Impact Factor
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    ABSTRACT: The goal of molecular cytogenetic testing for children presenting with developmental delay (DD) is to identify or exclude genetic abnormalities that are associated with cognitive, behavioral and/or motor symptoms. Until 2010, chromosome analysis was the standard first-line genetic screening test for evaluation of patients with DD when a specific syndrome was not suspected. In 2010, The American College of Medical Genetics and several other groups recommended chromosomal microarray as the first-line test in children with DDs, multiple congenital anomalies and/or autism. This test is able to detect regions of genomic imbalances at a much finer resolution than G-banded karyotyping. Until recently, no chromosomal microarray testing had been approved by the US FDA. This article focuses on the use of the Affymetrix CytoScan® Dx Assay (Santa Clara, CA, USA), the first chromosomal microarray to receive FDA approval for the genetic evaluation of individuals with DD.
    Expert Review of Molecular Diagnostics 10/2014; 15(2). DOI:10.1586/14737159.2015.975213 · 4.27 Impact Factor
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    ABSTRACT: Autism spectrum disorder (ASD) and intellectual disability (ID) can be caused by mutations in a large number of genes. One example is SHANK3 on the terminal end of chromosome 22q. Loss of one functional copy of SHANK3 results in 22q13 deletion syndrome or Phelan-McDermid syndrome (PMS) and causes a monogenic form of ASD and/or ID with a frequency of 0.5% to 2% of cases. SHANK3 is the critical gene in this syndrome, and its loss results in disruption of synaptic function. With chromosomal microarray analyses now a standard of care in the assessment of ASD and developmental delay, and with the emergence of whole exome and whole genome sequencing in this context, identification of PMS in routine clinical settings will increase significantly. However, PMS remains a rare disorder, and the majority of physicians have never seen a case. While there is agreement about core deficits of PMS, there have been no established parameters to guide evaluation and medical monitoring of the syndrome. Evaluations must include a thorough history and physical and dysmorphology examination. Neurological deficits, including the presence of seizures and structural brain abnormalities should be assessed as well as motor deficits. Endocrine, renal, cardiac, and gastrointestinal problems all require assessment and monitoring in addition to the risk of recurring infections, dental and vision problems, and lymphedema. Finally, all patients should have cognitive, behavioral, and ASD evaluations. The objective of this paper is to address this gap in the literature and establish recommendations to assess the medical, genetic, and neurological features of PMS.
    Journal of Neurodevelopmental Disorders 10/2014; 6(1):39. DOI:10.1186/1866-1955-6-39 · 3.71 Impact Factor
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    ABSTRACT: The RASopathies are a relatively common group of phenotypically similar and genetically related autosomal dominant genetic syndromes caused by missense mutations affecting genes participating in the RAS/mitogen-activated protein kinase (MAPK) pathway that include Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome). NS and NSML can be difficult to differentiate during infancy, but the presence of multiple lentigines, café au lait spots, and specific cardiac defects facilitate the diagnosis. Furthermore, individual PTPN11 missense mutations are highly specific to each syndrome and engender opposite biochemical alterations on the function of SHP-2, the protein product of that gene. Here, we report on a 5-year-old male with two de novo PTPN11 mutations in cis, c.1471C>T (p.Pro491Ser), and c.1492C>T (p.Arg498Trp), which are associated with NS and NSML, respectively. This boy's phenotype is intermediate between NS and NSML with facial dysmorphism, short stature, mild global developmental delay, pulmonic stenosis, and deafness but absence of café au lait spots or lentigines. The double-mutant SHP-2 was found to be catalytically impaired. This raises the question of whether clinical differences between NS and NSML can be ascribed solely to the relative SHP-2 catalytic activity. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2014; 164A(9). DOI:10.1002/ajmg.a.36620 · 2.05 Impact Factor
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    ABSTRACT: Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of dyskeratosis congenita (DC), characterized by cerebellar hypoplasia, microcephaly, intrauterine growth retardation, and severe immunodeficiency in addition to features of DC. Germline mutations in the RTEL1 gene have recently been identified as causative of HH.
    Clinical Genetics 07/2014; DOI:10.1111/cge.12459 · 3.65 Impact Factor
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    ABSTRACT: Whole exome and genome sequencing (WES/WGS) is now routinely offered as a clinical test by a growing number of laboratories. As part of the test design process each laboratory must determine the performance characteristics of the platform, test and informatics pipeline. This report documents one such characterization of WES/WGS. Whole exome and whole genome sequencing was performed on multiple technical replicates of five reference samples using the Illumina HiSeq 2000/2500. The sequencing data was processed with a GATK-based genome analysis pipeline to evaluate: intra-run, inter-run, inter-mode, inter-machine and inter-library consistency, concordance with orthogonal technologies (microarray, Sanger) and sensitivity and accuracy relative to known variant sets. Concordance to high-density microarrays consistently exceeds 97% (and typically exceeds 99%) and concordance between sequencing replicates also exceeds 97%, with no observable differences between different flow cells, runs, machines or modes. Sensitivity relative to high-density microarray variants exceeds 95%. In a detailed study of a 129 kb region, sensitivity was lower with some validated single-base insertions and deletions "not called". Different variants are "not called" in each replicate: of all variants identified in WES data from the NA12878 reference sample 74% of indels and 89% of SNVs were called in all seven replicates, in NA12878 WGS 52% of indels and 88% of SNVs were called in all six replicates. Key sources of non-uniformity are variance in depth of coverage, artifactual variants resulting from repetitive regions and larger structural variants.
    BMC Medical Genomics 04/2014; 7(1):20. DOI:10.1186/1755-8794-7-20 · 3.91 Impact Factor
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    ABSTRACT: Steroidogenic factor 1 (SF1) is a nuclear receptor encoded by the NR5A1 gene. SF1 affects both sexual and adrenal development through the regulation of target gene expression. Genotypic male and female SF1 knockout mice have adrenal and gonadal agenesis with persistent Müllerian structures and early lethality. There have been several reports of NR5A1 mutations in individuals with 46,XY complete gonadal dysgenesis (CGD) or other disorders of sexual development (DSD) with or without an adrenal phenotype. To date microdeletions involving NR5A1 have been reported in only two patients with DSDs. We report a novel microdeletion encompassing NR5A1 in a patient with 46,XY DSD and developmental delay. The phenotypically female patient initially presented with mild developmental delay and dysmorphisms. Chromosome analysis revealed a 46,XY karyotype. A 1.54 Mb microdeletion of chromosome 9q33.3 including NR5A1 was detected by array CGH and confirmed by FISH. Normal maternal FISH results indicated that this was most likely a de novo event. Since most NR5A1 mutations have been ascertained through gonadal or adrenal abnormalities, the additional findings of developmental delay and minor facial dysmorphisms are possibly related to haploinsufficiency of other genes within the 1.54 Mb deleted region. This report further confirms the role of NR5A1 deletions in 46,XY DSD and reinforces the utility of aCGH in the work up of DSDs of unclear etiology.
    European journal of medical genetics 09/2013; 56(11). DOI:10.1016/j.ejmg.2013.09.006 · 1.49 Impact Factor
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    ABSTRACT: -Human genomes harbor copy number variants (CNVs), regions of DNA gains or losses. While pathogenic CNVs are associated with congenital heart disease (CHD), their impact on clinical outcomes is unknown. This study sought to determine whether pathogenic CNVs among infants with single ventricle (SV) physiology were associated with inferior neurocognitive and somatic growth outcomes. -Genomic DNAs from 223 subjects of two National Heart, Lung, and Blood Institute-sponsored randomized clinical trials with infants with SV CHD and 270 controls from The Cancer Genome Atlas project were analyzed for rare CNVs >300 kb using array comparative genomic hybridization. Neurocognitive and growth outcomes at 14 months from the CHD trials were compared among subjects with and without pathogenic CNVs. Putatively pathogenic CNVs, comprising 25 duplications and 6 deletions, had a prevalence of 13.9%, significantly greater than the 4.4% rate of such CNVs among controls. CNVs associated with genomic disorders were found in 13 cases but no control. Several CNVs likely to be causative of SV CHD were observed, including aberrations altering the dosage of GATA4, MYH11, and GJA5. Subjects with pathogenic CNVs had worse linear growth, and those with CNVs associated with known genomic disorders had the poorest neurocognitive and growth outcomes. A minority of children with pathogenic CNVs were noted to be dysmorphic on clinical genetics examination. -Pathogenic CNVs appear to contribute to the etiology of SV forms of CHD in at least 10% of cases, are clinically subtle but adversely affect outcomes in children harboring them.
    Circulation Cardiovascular Genetics 09/2013; 6(5). DOI:10.1161/CIRCGENETICS.113.000189 · 5.34 Impact Factor
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    ABSTRACT: Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2,017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria.
    Clinical Genetics 08/2013; 86(2). DOI:10.1111/cge.12247 · 3.65 Impact Factor
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    ABSTRACT: The breast and ovarian cancer susceptibility gene (BRCA1) encodes a tumor suppressor. The BRCA1 protein is found primarily in cell nuclei and plays an important role in the DNA damage response and transcriptional regulation. Deficiencies in DNA repair capabilities have been associated with higher histopathological grade and worse prognosis in breast cancer. In order to investigate the subcellular distribution of BRCA1 in tumor tissue we randomly selected 22 breast carcinomas and tested BRCA1 protein localization in frozen and contiguous formalin-fixed, paraffin embedded (FFPE) tissue, using pressure cooker antigen-retrieval and the MS110 antibody staining. To assess the impact of BRCA1 germline mutations on protein localization, we retrospectively tested 16 of the tumor specimens to determine whether they contained the common Ashkenazi Jewish founder mutations in BRCA1 (185delAG, 5382insC), and BRCA2 (6174delT). We also compared co-localization of BRCA1 and nucleolin in MCF7 cells (wild type) and a mutant BRCA1 cell line, HCC1937 (5382insC). In FFPE tissue, with MS110 antibody staining, we frequently found reduced BRCA1 nuclear staining in breast tumor tissue compared to normal tissue, and less BRCA1 staining with higher histological grade in the tumors. However, in the frozen sections, BRCA1 antibody staining showed punctate, intra-nuclear granules in varying numbers of tumor, lactating, and normal cells. Two mutation carriers were identified and were confirmed by gene sequencing. We have also compared co-localization of BRCA1 and nucleolin in MCF7 cells (wild type) and a mutant BRCA1 cell line, HCC1937 (5382insC) and found altered sub-nuclear and nucleolar localization patterns consistent with a functional impact of the mutation on protein localization. The data presented here support a role for BRCA1 in the pathogenesis of sporadic and inherited breast cancers. The use of well-characterized reagents may lead to further insights into the function of BRCA1 and possibly the further development of targeted therapeutics.
    Cancer Cell International 07/2013; 13(1):70. DOI:10.1186/1475-2867-13-70 · 1.99 Impact Factor
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    ABSTRACT: Purpose:Spinal muscular atrophy is a common autosomal-recessive disorder caused by mutations of the SMN1 gene. Spinal muscular atrophy carrier screening uses dosage-sensitive methods that determine SMN1 copy number, and the frequency of carriers varies by ethnicity, with detection rates ranging from 71 to 94% due to the inability to identify silent (2 + 0) carriers with two copies of SMN1 on one chromosome 5 and deletion on the other. We hypothesized that identification of deletion and/or duplication founder alleles might provide an approach to identify silent carriers in various ethnic groups.Methods:SMN1 founder alleles were investigated in the Ashkenazi Jewish population by microsatellite analysis and next-generation sequencing.Results:An extended haplotype block, specific to Ashkenazi Jewish SMN1 duplications, was identified by microsatellite analysis, and next-generation sequencing of SMN1 further defined a more localized haplotype. Of note, six novel SMN1 sequence variants were identified that were specific to duplications and not present on single-copy alleles. The haplotype was also identified on SMN1 duplication alleles in additional ethnic groups.Conclusion:Identification of these novel variants in an individual with two copies of SMN1 significantly improves the accuracy of residual risk estimates and has important implications for spinal muscular atrophy carrier screening.Genet Med advance online publication 20 June 2013Genetics in Medicine (2013); doi:10.1038/gim.2013.84.
    Genetics in medicine: official journal of the American College of Medical Genetics 06/2013; 16(2). DOI:10.1038/gim.2013.84 · 6.44 Impact Factor
  • Ninette Cohen, Lisa Edelmann
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    ABSTRACT: Assessing the fetal karyotype is possible through procedures, such as amniocentesis and chorionic villus sampling, which allow the isolation of cell lines that are fetal in origin. Although aneuploidies are by far the most common chromosome abnormalities that lead to birth defects, a number of structural chromosome rearrangements can be identified by standard karyotype analysis. They include translocations, inversions, and supernumerary marker chromosomes. When balanced and inherited from a normal parent, these aberrations are generally not associated with a clinical phenotype; however, when de novo in origin, they have certain empirical risks. Molecular cytogenetic technologies, such as fluorescence in situ hybridization (FISH), can help to elucidate and further define fetal chromosome abnormalities. Cytogenomic techniques, such as array comparative genomic hybridization, can examine the genome at much higher resolution than karyotyping and FISH and are currently used as additional testing when ultrasound abnormalities are present with a normal karyotype as well as follow-up to abnormal karyotypes that involve de novo aberrations and material of unknown origin.
    Molecular Genetic Pathology, 01/2013: pages 517-527; , ISBN: 978-1-4614-4799-3
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    ABSTRACT: To determine the role of CYP450 copy number variation (CNV) beyond CYP2D6, 11 CYP450 genes were interrogated by multiplex ligation-dependent probe amplification and quantitative PCR in 542 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish individuals. The CYP2A6, CYP2B6 and CYP2E1 combined deletion/duplication allele frequencies ranged from 2 to 10% in these populations. High-resolution microarray-based comparative genomic hybridization (aCGH) localized CYP2A6, CYP2B6 and CYP2E1 breakpoints to directly oriented low-copy repeats. Sequencing localized the CYP2B6 breakpoint to a 529-bp intron 4 region with high homology to CYP2B7P1, resulting in the CYP2B6*29 partial deletion allele and the reciprocal, and novel, CYP2B6/2B7P1 duplicated fusion allele (CYP2B6*30). Together, these data identified novel CYP450 CNV alleles (CYP2B6*30 and CYP2E1*1Cx2) and indicate that common CYP450 CNV formation is likely mediated by non-allelic homologous recombination resulting in both full gene and gene-fusion copy number imbalances. Detection of these CNVs should be considered when interrogating these genes for pharmacogenetic drug selection and dosing.The Pharmacogenomics Journal advance online publication, 20 November 2012; doi:10.1038/tpj.2012.48.
    The Pharmacogenomics Journal 11/2012; 13(6). DOI:10.1038/tpj.2012.48 · 5.51 Impact Factor
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    ABSTRACT: The chromosome 22q11.2 region is commonly involved in non-allelic homologous recombination (NAHR) events. Microduplications of 22q11.2, usually involving a 3 Mb or 1.5 Mb region constitute the 22q11 microduplication syndrome. Both microdeletions and microduplications of 22q11.21 are reported to share several phenotypic characteristics, including dysmorphic facial features, velopharyngeal insufficiency, congenital heart disease, urogenital abnormalities, and immunologic defects. We report a child who presented at 8 months of age for evaluation of microcephaly and mild motor delay. Head circumference at birth, at 8 months, and at 19 months of age was below the 3(rd) centile. Other findings included left-sided cryptorchidism and developmental dysplasia of the left hip. In addition, echocardiography revealed a restrictive patent ductus arteriosus. Chromosomal microarray analysis using Affymetrix Genome-Wide Human SNP Array 6.0 revealed a novel 437 kb interstitial duplication at 22q11.21, involving TBX1, whose breakpoints did not coincide with known low copy repeat (LCR) regions. The same duplication was confirmed by fluorescent in situ hybridization (FISH) in the patient's mother and an older sister. The mother has a history of anxiety disorder and depression. The sister had a history of delayed motor milestones. None of the three duplication carriers has any documented renal anomalies or other significant medical problems. This report demonstrates the clinical heterogeneity associated with microduplications of 22q11.2 and illustrates the difficulties related to providing prognostic information and accurate genetic counseling to families when this finding is detected. The described microduplication is the smallest in this genomic region reported to date and further implicates abnormal gene dosage of TBX1 in disorders resulting from 22q11.2 rearrangements.
    European journal of medical genetics 10/2012; 55(12). DOI:10.1016/j.ejmg.2012.08.011 · 1.49 Impact Factor
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    ABSTRACT: Autism spectrum disorders (ASDs) are phenotypically complex developmental neuropsychiatric disorders affecting approximately 0.6% of the population. About 30-70% of affected children are also considered to have intellectual disability (ID). The underlying genetic causes of ASDs are diverse with a defined etiology in 16-20%. Array comparative genomic hybridization (aCGH) has proven useful in identifying sub-microscopic chromosome aberrations in a subset of patients, some of which have been shown to be recurrent. One such aberration is the 1.4 Mb microdeletion at chromosome 17q12, which has been reported to be associated with renal disease, growth restriction, diabetes, cognitive impairment, seizures, and in some cases an ASD. Patients with the reciprocal chromosome 17q12 microduplication typically have also been identified with ID and in some cases seizures and behavioral abnormalities. Here we report a patient with a de novo, 1.4 Mb microduplication diagnosed with significant ID involving complex deficits and autism. To our knowledge, this is the first report of a patient with the 17q12 microduplication and a complex ASD phenotype.
    American Journal of Medical Genetics Part A 05/2012; 158A(5):1170-7. DOI:10.1002/ajmg.a.35267 · 2.05 Impact Factor
  • Abigail E Southard, Lisa J Edelmann, Bruce D Gelb
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    ABSTRACT: Human genomes include copy number variants (CNVs), defined as regions with DNA gains or losses. Pathologic CNVs, which are larger and often occur de novo, are increasingly associated with disease. Given advances in genetic testing, namely microarray-based comparative genomic hybridization and single nucleotide polymorphism arrays, previously unidentified genotypic aberrations can now be correlated with phenotypic anomalies. The objective of this study was to conduct a nonsystematic literature review to document the role of CNVs as they relate to isolated structural anomalies of the craniofacial, respiratory, renal, and cardiac systems. All full-length articles in the PubMed database through May 2011 that discussed CNVs and isolated structural defects of the craniofacial, respiratory, renal, and cardiac systems were considered. Search terms queried include CNV, copy number variation, array comparative genomic hybridization, birth defects, craniofacial defects, respiratory defects, renal defects, and congenital heart disease. Reports published in languages other than English and articles regarding CNVs and neurocognitive deficits were not considered. Evidence supports that putatively pathogenic CNVs occur at an increased frequency in patients with isolated structural birth defects and implicate specific regions of the genome. Through CNV detection, advances have been made in identifying genes and specific loci that underlie isolated birth defects. Although limited studies have been published, the promising evidence reviewed here warrants the continued investigation of CNVs in children with isolated structural birth defects. Patient care and genetic counseling stand to improve through a better understanding of CNVs and their effect on disease phenotype.
    PEDIATRICS 03/2012; 129(4):755-63. DOI:10.1542/peds.2011-2337 · 5.30 Impact Factor
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    ABSTRACT: To determine if copy number variants contribute to warfarin dose requirements, we investigated CYP2C9, VKORC1, CYP4F2, GGCX and CALU for deletions and duplications in a multiethnic patient population treated with therapeutic doses of warfarin. DNA samples from 178 patients were subjected to copy number analyses by multiplex ligation-dependent probe amplification or quantitative PCR assays. Additionally, the CYP2C9 exon 8 insertion/deletion polymorphism (rs71668942) was examined among the patient cohort and 1750 additional multiethnic healthy individuals. All patients carried two copies of CYP2C9 by multiplex ligation-dependent probe amplification and no exon 8 deletion carriers were detected. Similarly, quantitative PCR assays for VKORC1, CYP4F2, GGCX and CALU identified two copies in all populations. These data indicate that copy number variants in the principal genes involved in warfarin dose variability (CYP2C9, VKORC1), including genes with lesser effect (CYP4F2, GGCX), and those that may be more relevant among certain racial groups (CALU), are rare in multiethnic populations, including African-Americans.
    Pharmacogenomics 12/2011; 13(3):297-307. DOI:10.2217/pgs.11.156 · 3.43 Impact Factor
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    ABSTRACT: The success of prenatal carrier screening as a disease prevention strategy in the Ashkenazi Jewish (AJ) population has driven the expansion of screening panels as disease-causing founder mutations have been identified. However, the carrier frequencies of many of these mutations have not been reported in large AJ cohorts. We determined the carrier frequencies of over 100 mutations for 16 recessive disorders in the New York metropolitan area AJ population. Among the 100% AJ-descended individuals, screening for 16 disorders resulted in ∼1 in 3.3 being a carrier for one disease and ∼1 in 24 for two diseases. The carrier frequencies ranged from 0.066 (1 in 15.2; Gaucher disease) to 0.006 (1 in 168; nemaline myopathy), which averaged ∼15% higher than those for all screenees. Importantly, over 95% of screenees chose to be screened for all possible AJ diseases, including disorders with lower carrier frequencies and/or detectability. Carrier screening also identified rare individuals homozygous for disease-causing mutations who had previously unrecognized clinical manifestations. Additionally, prenatal testing results and experience for all 16 disorders (n = 574) are reported. Together, these data indicate the general acceptance, carrier frequencies, and prenatal testing results for an expanded panel of 16 diseases in the AJ population.
    Human Mutation 11/2010; 31(11):1240-50. DOI:10.1002/humu.21327 · 5.05 Impact Factor
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    ABSTRACT: Type 1 Gaucher disease (GD), an autosomal recessive lysosomal storage disease, is most prevalent in the Ashkenazi Jewish (AJ) population. Experts have suggested that up to two-thirds of AJ homozygotes for the common mutation (N370S) are asymptomatic throughout life and never come to medical attention. However, there are no systematic studies of N370S homozygotes to support this presumption. Prenatal carrier screening of 8069 AJ adults for 6 common GD mutations was performed. Gaucher disease manifestations in 37 previously unrecognized homozygotes were assessed by clinical, laboratory, and imaging studies. Among the 8069 AJ screenees, 524 GD carriers (1:15) and 9 previously unrecognized GD homozygotes (1:897) were identified, consistent with the rate expected (1:949; P > .99). Six of these homozygotes and 31 AJ GD homozygotes identified by other prenatal carrier screening programs in the New York City metropolitan area were evaluated (age range of the homozygotes, 17-40 years). Of these, 84% were N370S homozygotes, others being heteroallelic for N370S and V394L, L444P, or R496H mutations. Notably, 65% reported no GD medical complaints. However, 49% had anemia and/or thrombocytopenia. Among the 29 who had imaging studies, 97% had mild to moderate splenomegaly and 55% had hepatomegaly; skeletal imaging revealed marrow infiltration (100%), Erlenmeyer flask deformities (43%), lucencies (22%), and bone infarcts (14%). Dual energy X-ray absorptiometry studies of 25 homozygotes found 60% with osteopenia or osteoporosis. Contrary to previous discussions, almost all asymptomatic GD homozygotes serendipitously diagnosed by prenatal carrier screening had disease manifestations and should be followed for disease progression and institution of appropriate medical treatment.
    Archives of internal medicine 09/2010; 170(16):1463-9. DOI:10.1001/archinternmed.2010.302 · 13.25 Impact Factor
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    ABSTRACT: Turner syndrome (TS) results from whole or partial monosomy X and is mediated by haploinsufficiency of genes that normally escape X-inactivation. Although a 45,X karyotype is observed in half of all TS cases, the most frequent variant TS karyotype includes the isodicentric X chromosome alone [46,X,idic(X)(p11)] or as a mosaic [46,X,idic(X)(p11)/45,X]. Given the mechanism of idic(X)(p11) rearrangement is poorly understood and breakpoint sequence information is unknown, this study sought to investigate the molecular mechanism of idic(X)(p11) formation by determining their precise breakpoint intervals. Karyotype analysis and fluorescence in situ hybridization mapping of eight idic(X)(p11) cell lines and three unbalanced Xp11.2 translocation lines identified the majority of breakpoints within a 5 Mb region, from approximately 53 to 58 Mb, in Xp11.1-p11.22, clustering into four regions. To further refine the breakpoints, a high-resolution oligonucleotide microarray (average of approximately 350 bp) was designed and array-based comparative genomic hybridization (aCGH) was performed on all 11 idic(X)(p11) and Xp11.2 translocation lines. aCGH analyses identified all breakpoint regions, including an idic(X)(p11) line with two potential breakpoints, one breakpoint shared between two idic(X)(p11) lines and two Xp translocations that shared breakpoints with idic(X)(p11) lines. Four of the breakpoint regions included large inverted repeats composed of repetitive gene clusters and segmental duplications, which corresponded to regions of copy-number variation. These data indicate that the rearrangement sites on Xp11.2 that lead to isodicentric chromosome formation and translocations are probably not random and suggest that the complex repetitive architecture of this region predisposes it to rearrangements, some of which are recurrent.
    Human Molecular Genetics 09/2010; 19(17):3383-93. DOI:10.1093/hmg/ddq250 · 6.68 Impact Factor

Publication Stats

1k Citations
276.83 Total Impact Points

Institutions

  • 2001–2015
    • Icahn School of Medicine at Mount Sinai
      • • Department of Pathology
      • • Department of Genetics and Genomic Sciences
      Borough of Manhattan, New York, United States
  • 2008–2013
    • NYU Langone Medical Center
      New York, New York, United States
    • Mount Sinai Medical Center
      New York, New York, United States
  • 2005
    • Albert Einstein College of Medicine
      • Department of Cell Biology
      New York City, NY, United States
  • 2002
    • CUNY Graduate Center
      New York, New York, United States